Transcription factors in islet development and physiology: role of PDX-1 in beta-cell function

Differentiation of early foregut endoderm into pancreatic endocrine and exocrine cells depends on a cascade of gene activation events controlled by various transcription factors. The first molecular marker identified that specifies the early pancreatic epithelium is the homeodomain-containing transcription factor PDX-1. Its absence in mice and humans during development leads to agenesis of the pancreas. Later, it becomes restricted primarily to beta cells where it regulates the expression of beta cell-specific genes, and, most importantly, mediates the glucose effect on insulin gene transcription. Although exposure of beta cells to high glucose concentrations for relatively short periods stimulates insulin gene expression, chronic exposure has adverse effects on many beta-cell functions, including insulin gene transcription. These events appear to correlate with pdx-1 gene expression and its ability to bind the insulin gene. We consider that loss of PDX-1 function or altered pdx-1 gene expression due to mutations or functional impairment of transcription factors controlling its expression can lead to diabetes.